Artificial blood vessels are frequently used in surgical vascular reconstruction for treatment of diseases such as arteriosclerosis obliterans, aortic aneurysm and aortic dissection. In addition, balloon catheters and stents are frequently used to dilate occluded blood vessels. However, vessels frequently become reoccluded following surgery using these devices, thereby resulting in the problem of having to repeat the same procedure.
For example, although surgical vascular reconstruction is used to avoid amputation of a lower limb for patients with arteriosclerosis obliterans, bypass surgery using an artificial blood vessel is the first choice of treatment for lesions above the knee. However, occlusion of the artificial vessel may occur later than one month after surgery. This occlusion is mainly caused by thickening of the vascular intima at the anastomosed site. Inhibiting this thickening would make it possible to conserve grafts for a long period of time as well as to use artificial blood vessels for vascular reconstruction at locations below the knee.
The major cause of thickening of vascular intima at anastomosed sites of artificial blood vessels is the activation of cell proliferation by an inflammatory reaction occurring at the anastomosed site. Thus, inhibition of this cell proliferation is thought to be able to inhibit thickening.
Gene therapy techniques have been developed in recent years for the purpose of inhibiting inflammatory reactions.
Research has been conducted which is expected to demonstrate anti-inflammatory effects by inhibiting the function of NF-κB, a transcriptional regulatory factor involved in inflammatory reactions, with a decoy nucleic acid.
International Patent Publication No. (WO-A1) 96/035430 discloses that an NF-κB decoy nucleic acid can be a therapeutic agent for inflammatory diseases.
In addition, gene therapy techniques for controlling cell proliferation have also been developed. For example, the proliferation of vascular media can be inhibited by inhibiting the function of E2F, a transcriptional regulatory factor that plays an important role in cell proliferation, with a decoy nucleic acid.
JP-B 3392143 discloses an anticancer agent with the use of an E2F decoy nucleic acid.
WO 95/11687 discloses that cell proliferation can be inhibited by using an E2F decoy nucleic acid.
Previously disclosed examples of oligonucleotides having two different functions within a single molecule are indicated below.
JP-A(W) 2002-515514 discloses a method for using an ICAM-1 antisense as an external skin medication, and although it is stated that it may have a DNA: RNA or RNA: DNA chimeric structure, there are no specific examples of chimera decoys indicated, including cited references. In addition, this publication discloses an invention relating to transdermal delivery of an antisense strand.
US-A 2003-176376 discloses that a hybrid molecule of a bcl-2 antisense and CRE decoy has the potential for treating diseases caused by abnormal cell growth such as cancer.
JP-A 2002-193813 indicates that a chimera decoy of NF-κB and Ets inhibits increase of aorta surface area in an aortic aneurysm model.